The present invention relates to drug particles and methods for their preparation. More particularly, the present invention relates to the preparation of drug particles utilizing evaporative precipitation into aqueous solutions.
Bioavailability is a term meaning the degree to which a drug becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.
It is known that the rate of dissolution of a particulate drug can increase with increasing surface area, that is, decreasing particle size. Efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, wet milling techniques have been used, as described in U.S. Pat. No. 5,145,684. However, such wet milling techniques exhibit problems associated with contamination from the grinding media. It is difficult to produce highly uniform submicron particles with wet milling and solids milling, and handling can be time consuming. Moreover, exposing a drug substance to mechanical shear or high temperatures for prolonged periods can cause the drug to lose its activity.
Spray drying into vapor is another method used to form micron sized drug particles. Spray drying is used commonly to formulate dry pharmaceutical powder. In most cases, either hydrophilic drugs in aqueous solution or poorly water soluble drugs in organic solution are sprayed, which approaches do not offer a means to simultaneously spray a poorly water soluble drug and water soluble excipient.
U.S. Pat. No. 5,985,248 teaches dissolving a hydrophilic excipient, or stabilizer, and a hydrophobic drug in a cosolvent system such as water:ethanol, and spray drying the system into vapor. U.S. Pat. No. 6,001,336 teaches suspending a hydrophobic drug in an aqueous solution containing a hydrophilic stabilizer, and spray drying the suspension into vapor. U.S. Pat. No. 6,077,543 and WO 98/29096 teach atomizing an organic and an aqueous solution together into a vapor. In all of these teachings, drug particles in the micron size range are formed. It is difficult to produce sub-micron particles by these technique due to growth of the drug particles during the solvent evaporation. As the water evaporates it will no longer solvate hydrophilic stabilizers. Solvation of the stabilizer is needed for it to be able to prevent growth of the drug particles. As a result, growth of the drug particles is not likely to be inhibited by the stabilizer and the particle size is typically greater than 1 micron. Moreover, in all of these teachings, the precipitation of surfactant and stabilizers occur simultaneously in the coaxial nozzle, and it is much more difficult to control the particle morphology. Furthermore, in all of these teachings, the useful excipients are sugars, salts, pectin and citric acid, which are not good stabilizers for preventing growth of particles during the spray process.
U.S. Pat. Nos. 5,795,594 and 5,851,453 teach the use of compressed fluid antisolvents to form drug particles in the micron-size range. This process has been called Precipitation using Compressed Antisolvents (PCA), Solution-Enhanced Dispersion of Solids (SEDS) and Supercritical AntiSolvent process (SAS). In most cases this process does not utilize water due to the low solubility of water in compressed carbon dioxide, so that it is difficult to use water-soluble excipients with this process. However, in some cases, this process is able to use water by flowing an organic drug solution, an aqueous solution and a second organic solvent such as ethanol into compressed carbon dioxide. The ethanol is needed to extract the water into the CO2 phase. In this process it is difficult to control the particle size due to the complexity of the mixing of the three streams in the jet. Also, the particles must be recovered from a high pressure vessel, and high ratios of CO2 to drug are necessary. Moreover, as the water contacts CO2, the pH in the water reaches about 3, which can be detrimental to drug stability and interactions with excipients.
Young et al., Rapid Expansion from Supercritical to Aqueous Solution to Produce Submicron Suspensions of Water-Insoluble Drugs, Biotechnol. Prog. 2000, 16, 402-407, teach the formation of poorly water soluble drug particles by rapid expansion of supercritical fluid solutions into water. The supercritical fluid was carbon dioxide above its critical temperature. The solubility of drugs in carbon dioxide and other supercritical fluids such as ethane and propane is typically very small. It is difficult to add water soluble stabilizers and excipients in spray antisolvent processes (PCA, SAS or SEDS) into carbon dioxide due to the low solubility of water in CO2. Reverchon E., Supercritical Antisolvent Precipitation of Micro-and Nano-particles, J. Supercrit. Fluid., 1999, 15, 1-21. These antisolvent processes require large ratios of carbon dioxide to drug and the use of a high pressure vessel for recovery of product. Even when an aqueous and two organic solutions are sprayed through a coaxial nozzle, the process is subject to many of the limitations discussed above for spray drying organic and aqueous phases through coaxial nozzles. As the water dissolves into the ethanol-carbon dioxide mixture, it is no longer available to solvate stabilizers to prevent particle growth. Therefore this process is limited to relatively few drugs.
It would be an advantage in the art of preparation of drug particles to provide a method which allows for easy control of particle size and morphology and which is applicable to a wide breadth of drug substances.
In one aspect, the present invention is a method for preparing poorly water soluble drug particles comprising the steps of dissolving a drug in at least one organic solvent to form a drug/organic mixture; spraying the drug/organic mixture into an aqueous solution; and concurrently evaporating the organic solvent in the presence of the aqueous solution to form an aqueous dispersion of the drug particles.
In a second aspect, the present invention is poorly water soluble drug particles having an average particle diameter of from 50 nanometers to 20 microns, the drug particles being prepared by a process comprising the steps of dissolving the drug in at least one organic solvent to form a drug/organic mixture; spraying the drug/organic mixture into an aqueous solution; and concurrently evaporating the organic solvent in the presence of the aqueous solution to form an aqueous dispersion of the drug particles.
The present invention utilizes evaporative precipitation into aqueous solutions (EPAS) to form micron to sub-micron sized drug particles, leading to increased bioavailability relative to larger particles. The process of the present invention has applicability to a wide range of drug substances as several solvents may be chosen to dissolve the drug. The ability to utilize poorly soluble drugs and water soluble stabilizers/excipients offers the ability to form submicron particles that have high dissolution rates in aqueous media. The present invention also offers the ability to better control the resulting particle size and morphology relative to techniques described in the above identified prior art. Moreover, the present invention often produces particles having reduced crystallinity as compared to the bulk, unprocessed drug, which enhances dissolution.